Elevated Plasma Adrenocorticotropic Hormone Research Articles

7372 Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Polycystic Ovarian Syndrome (PCOS)

Abstract Disclosure: H. Pan: None. L.L. Liu: None. Q. Lv: None. F.G. Grosveld: None. D. Drabek: None. R.V. Haperen: None. X. Wang: None. Y. He: None. Y. Wang: None. J. Huang: None. J. Lee: None. G. Zhang: None. J.J. Rong: None. H.V. Chen: None. J.A. Majzoub: Advisory Board Member; Self; Chair of SAB of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. Stock Owner; Self; Equity Owner of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. J.J. Zhao: None. Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 for the Treatment of Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovarian Syndrome (PCOS). Abstract Congenital Adrenal Hyperplasia (CAH) is a rare autosomal recessive genetic disease due to mutation of CYP21A2 which leads to deficiency of 21-Hydroxylase enzymatic activity. Classical CAH patients are born with life-threatening deficiency of glucocorticoid (GC) and mineralocorticoid. Due to this enzymatic block and the lack of negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis by GC, the adrenal gland produces excessive amounts of androgen which result in masculinized genitalia and virilization. The current standard care is supraphysiological doses of GC, which are difficult to balance between excess GC exposure and excess androgen secretion. Too little GC does not suppress production of androgen sufficiently and too much GC leads to Cushing Syndrome (CS). Previous work found that corticotropin-releasing hormone (CRH) is absolutely required for activation of the HPA axis during loss of GC negative feedback, via adrenocorticotropic hormone (ACTH) (1), which is necessary for production of adrenal androgens (2). We report here the development of Anti-CRH humanized monoclonal antibody HBM9013 (PR302334-24) for the treatment of CAH. HBM9013 binds to CRH with high affinity and neutralizes its signaling through both CRH Receptor 1 (CRHR1) and CRH Receptor 2 (CRHR2) in vitro. HBM9013 shows in vivo activities in two preclinical models. It blocks restraint stress-induced increases in plasma ACTH and corticosterone in mouse and rat. Mouse ACTH and Corticosterone were reduced from 210 ± 63 pg/ml to 27 ± 8 pg/ml (Mean ± SD, p = 5.2*10-6; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice) and from 303 ± 28 ng/ml to 57 ± 15 ng/ml (Mean ± SD, p = 6.2*10-[1][1]; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice), respectively. It also markedly reduces the constitutive, extremely elevated plasma ACTH levels in Mrap-knockout mice from 3847 ± 240 pg/mL to 1080 ± 302 pg/mL (Mean ± SD, n = 5 independent experiments, p = 2.3*10-7). HBM9013 has excellent CMC characteristics with ∼5 g/L titer and ∼80% yield. HBM9013 also has an excellent safety profile with no-observed-adverse-effect-level (NOAEL) of 150 mg/kg in weekly dosing for five doses in both rat and cynomolgus dose-ranging-finding (DRF) toxicology studies. HBM9013 is formulated up to 150 mg/ml as a weekly to monthly subcutaneous injection for ease of administration and compliance for CAH patient. HBM9013 could be a next generation therapy for CAH, in combination with a low physiological dose of GC that would avoid CS. Since ∼50% of Polycystic Ovarian Syndrome (PCOS) androgens may be of adrenal origin, we believe that HBM9013 could also be indicated for PCOS. References(1)Muglia LJ et al. J Clin Invest. 2000. 105:1269-77.(2)Weber A et al. Clin Endocrinol. 1997. 46:431-7. Presentation: 6/1/2024

Effects of chronic stress on rat heart function following regional ischemia: a sex-dependent investigation.

Chronic psychological stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 h of daily restraint stress for 4 wk versus matched controls, followed by euthanasia (sodium pentobarbital) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. When compared with controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (P < 0.05), whereas CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (P < 0.01) and reduced corticosterone (P < 0.001) alongside lower serum estradiol (P < 0.001) and estradiol/progesterone ratio (P < 0.01). Of note, CRS females showed increased serum cardiac troponin T (P < 0.05) and tumor necrosis factor-α (TNF-α) (P < 0.01) with suppressed interleukin (IL)-1α, IL-1β, IL-6, and IL-10 levels (P < 0.05) when compared with controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired postischemic functional recovery for baseline stroke volume (SV, P < 0.01), work performance (P < 0.05), aortic output (AO, P < 0.05), coronary flow (CF, P < 0.01), and overall cardiac output (CO, P < 0.01) when compared with matched controls and CRS males (P < 0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, proinflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.NEW & NOTEWORTHY Although chronic psychological stress is a risk factor for cardiovascular diseases, the underlying mechanisms remain poorly understood. This study revealed that chronic restraint stress resulted in systemic changes (dysregulated stress hormones, proinflammatory state) and potential cardiomyopathy in females versus controls and their male counterparts. The stressed female hearts also displayed reduced functional recovery following ex vivo ischemia-reperfusion. This highlights the importance of incorporating sex as a biological variable in cardiac research.

478. Elevated Plasma Adrenocorticotropic Hormone (ACTH) Levels Correlate With Reduced Suicidal Thoughts in Psychiatric Patients Relative to Control Groups, Regardless of Depression Intensity

478. Elevated Plasma Adrenocorticotropic Hormone (ACTH) Levels Correlate With Reduced Suicidal Thoughts in Psychiatric Patients Relative to Control Groups, Regardless of Depression Intensity

Adrenal Hemorrhaging in a Patient with Severe Obstructive Sleep Apnea Syndrome with Elevated Plasma ACTH Levels.

Adrenal hemorrhaging (AH) is a rare condition characterized by bleeding into the suprarenal glands. A 62-year-old man with untreated obstructive sleep apnea syndrome (OSAS) was admitted to our hospital complaining of abdominal stiffness. He was diagnosed with left-sided AH and underwent adrenalectomy. Pre- and post-surgery, elevated plasma adrenocorticotropic hormone (ACTH) levels were observed. However, Cushing's syndrome and adrenal insufficiency were negative, and nasal continuous positive airway pressure (CPAP) normalized the plasma ACTH levels. Elevated ACTH levels are reportedly present in patients with OSAS. ACTH may be associated with the development of AH through the change in blood supply and other mechanisms.

Seasonal variation of endogenous adrenocorticotropic hormone concentrations in healthy non-geriatric donkeys in Northern California

Elevated plasma adrenocorticotropic hormone (ACTH) is often used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. The hormone naturally increases in the fall in horses, and donkeys have been found to have higher ACTH concentrations than horses. However, circannual variation of ACTH has not been assessed in donkeys. The objective of the study was to establish seasonal variation of basal plasma ACTH concentrations over the course of a year in clinically healthy, non-geriatric donkeys. It was hypothesized that donkey ACTH concentrations would be higher than those reported in horses without PPID in all seasons, and that, similarly to horses, ACTH concentrations would further increase in the fall months. Twenty-six healthy adult donkeys (10 standards, 16 miniatures), a median (range) of 6 (2–13) years of age, were included. Donkeys were housed at a single location. Serial plasma samples were obtained monthly for 12 months. Plasma ACTH concentrations were determined by immunoassay. Data are presented as median (range), with a P-value < 0.05 considered significant. ACTH concentrations were lowest in the winter and spring [12.8 (5.0–73.6) pg/ml and 12.5 (2.8–62.6) pg/ml, respectively], with an increase in the summer [53.2 (29.7–305.0) pg/ml], and peak in the fall [77.1 (12.4–319.0) pg/ml]. ACTH concentrations were highest in the month of September [122.0 (41.7–319.0) pg/ml]. Donkey ACTH concentrations were higher than equine reference ranges from May through November but showed similar circannual variation with dramatic increases in the fall months. Species-specific reference ranges are necessary for accurate interpretation of endocrinopathy screenings in donkeys.

Refractory postoperative Staphylococcus hominis bacteremia in a patient with an ACTH-producing pancreatic neuroendocrine neoplasm: a case report

BackgroundStaphylococcus hominis (S. hominis) is an opportunistic pathogen that is often highly resistant to antibiotics and is difficult to treat. In patients diagnosed with an adrenocorticotropic hormone (ACTH)-producing tumor that compromises the immune system due to hypercortisolemia, cancer treatment and infection control should be considered simultaneously. This report presents a case of refractory postoperative S. hominis bacteremia requiring the prolonged administration of several antibiotics in a patient with an ACTH-producing pancreatic neuroendocrine neoplasm (pNEN).Case presentationA 35-year-old man visited a neighboring hospital for a thorough examination after experiencing weight gain and lower limb weakness for several months. Enhanced computed tomography revealed a pancreatic tail tumor and bilateral adrenal enlargement. Elevated plasma ACTH and serum cortisol were noted. Biopsy under endoscopic ultrasonography revealed the tumor as an ACTH-producing pNEN. The patient was transferred to our hospital for further treatment. Pneumocystis pneumonia was noted and treated with sulfamethoxazole and adjunctive glucocorticoids. Hypercortisolism was controlled with metyrapone and trilostane. Somatostatin receptor scintigraphy and ethoxybenzyl magnetic resonance imaging detected other lesions in the pancreatic head. A total pancreatectomy was performed given that the lesions were found in both the pancreatic head and tail. Plasma ACTH and serum cortisol levels decreased immediately after the resection. Pathological examination revealed that the pancreatic tail tumor was NEN G2 and T3N1aM0 Stage IIB and the pancreatic head lesions were SSTR-positive hyperplasia of the islet of Langerhans cells. On postoperative day 11, catheter-associated bacteremia occurred. Initially, meropenem hydrate and vancomycin hydrochloride were administered empirically. S. hominis was identified and appeared sensitive to these antibiotics according to susceptibility testing. However, S. hominis was repeatedly positive in blood cultures for more than one month, despite treatment with several antibiotics. Eventually, with the combined use of three antibiotics (meropenem hydrate, vancomycin hydrochloride, and clindamycin phosphate) for more than 3 weeks, the S. hominis-associated bacteremia improved. He was discharged 79 days after surgery.ConclusionsOur patient with an ACTH-producing pNEN was immunocompromised and needed meticulous attention for infectious complications even after successful tumor removal. Specifically, S. hominis bacteremia in such patients demands intensive treatments, such as with combinational antibiotics.

Concurrent mutations of germline GPR101 and somatic USP8 in a pediatric giant pituitary ACTH adenoma: a case report

BackgroundCushing’s disease (CD) is rare in pediatric patients. It is characterized by elevated plasma adrenocorticotropic hormone (ACTH) from pituitary adenomas, with damage to multiple systems and development. In recent years, genetic studies have shed light on the etiology and several mutations have been identified in patients with CD.Case presentationA girl presented at the age of 10 years and 9 months with facial plethora, hirsutism and acne. Her vision and eye movements were impaired. A quick weight gain and slow growth were also observed. Physical examination revealed central obesity, moon face, buffalo hump, supra-clavicular fat pads and bruising. Her plasma ACTH level ranged between 118 and 151 pg/ml, and sella enhanced MRI showed a giant pituitary tumor of 51.8 × 29.3 × 14.0 mm. Transsphenoidal pituitary debulk adenomectomy was performed and immunohistochemical staining confirmed an ACTH-secreting adenoma. Genetic analysis identified a novel germline GPR101 (p.G169R) and a somatic USP8 (p. S719del) mutation. They were hypothesized to impact tumor growth and function, respectively.ConclusionsWe reported a rare case of pediatric giant pituitary ACTH adenoma and pointed out that unusual concurrent mutations might contribute to its early onset and large volume.

Abstract #1165468: Stalk Effect: Cushing’s Disease Mistaken for Prolactinoma

The diagnostic workup for hypercortisolism is not infrequent in clinical practice. Common findings of high cortisol are weight gain, facial plethora, and menstrual irregularity. Here we discuss a distinct presentation of amenorrhea and galactorrhea as an unexpected exhibition of Cushing’s disease. A 35-year-old woman with a history of obesity presented with the chief complaint of infertility. Six months prior, she began to experience amenorrhea, galactorrhea, headaches, excessive sweating, and weight gain. Serum prolactin (PRL) level was found to be mildly elevated at 35.3 ng/mL. Magnetic resonance imaging (MRI) of the brain demonstrated a 11 mm x 9.8 mm x 9.6 mm pituitary macroadenoma. She was started on oral cabergoline 0.5 milligrams twice weekly for prolactinoma treatment, with resolution of all symptoms and return to normal PRL range. Tumor size on repeat MRI was stable. Six months later, she conceived. Cabergoline was stopped. She delivered a healthy infant but developed recurrence of her symptoms, now with diplopia. PRL was elevated at 61.9 ng/mL. Cabergoline was reinitiated. Further labs demonstrated elevated plasma adrenocorticotropic hormone (ACTH) of 121 pg/ml, elevated morning salivary cortisol of 0.217 ug/dL and elevated urinary free cortisol of 142 ug/24 hour. Overnight dexamethasone test showed unsuppressed cortisol. Cushing’s disease was diagnosed. Tumor size was 13 mm x 17 mm x 17 mm prior to surgical resection. Tumor pathology showed corticotroph adenoma. PRL highlighted in just a few scattered tumor cells. Her elevated prolactin levels were ultimately suspected to be due to stalk effect. Approximately 40% of all pituitary adenomas are prolactinomas. Clinical signs and symptoms of hyperprolactinemia include infertility, amenorrhea, and galactorrhea. Mild elevations of prolactin may cause infertility and can be consistent with prolactinoma. Amenorrhea associated with galactorrhea strongly suggests hyperprolactinemia. However, clinicians must note that in the presence of sellar mass and mild hyperprolactinemia, a non-prolactin-secreting mass must first be diagnostically ruled out. Cushing’s disease may present similarly with menstrual irregularities, hyperprolactinemia, and galactorrhea due to stalk effect. This patient demonstrated initial diagnostic uncertainty due to her incomplete workup and rapid clinical response to cabergoline. Her elevations in prolactin and response to cabergoline at the time of her original presentation may substantiate the proposed off-label use of dopamine agonists in non-prolactinoma pituitary tumors.

The role of pro-opiomelanocortin in the ACTH\u2013cortisol dissociation of sepsis

BackgroundSepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as ‘ACTH–cortisol dissociation.’ We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH–cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis.MethodsIn two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers.ResultsThe two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH–cortisol dissociation. Elevated plasma POMC and ACTH–corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05).ConclusionTogether, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH–cortisol dissociation.

Spontaneous Resolution of Primary Hypercortisolism of Cushing Disease After Pituitary Hemorrhage

To describe a case of spontaneous resolution of primary hypercortisolism from Cushing disease (CD) due to pituitary apoplexy (PA). Clinical, laboratory, and pathologic information are described. A 59-year-old female presented with a headache, a 2.3 cm sellar mass with a questionable hemorrhagic component, and clinical signs of hypercortisolism. On further evaluation, she had an increased 24-hour urine free cortisol, abnormal serum cortisol during a low dose dexamethasone suppression test, and an elevated plasma adrenocorticotropic hormone (ACTH), consistent with pituitary CD. As she was being prepared for surgical resection, she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism, and a repeat magnetic resonance imaging scan showed shrinkage of the sellar mass. She has been managed conservatively since and remains in clinical/biochemical remission until present time, 18 months following her initial presentation. We report a case of spontaneous resolution of CD from symptomatic hemorrhage within an ACTH-secreting pituitary adenoma, or PA. This has been rarely reported in the medical literature. The fact that she did not pass through a phase of adrenal withdrawal, makes us suspect a residual functional adenoma within or around the sella which may eventually grow, causing her disease to recur, as has been reported. Hence, continued monitoring will be required.

MON-317 Ectopic Cushing's Syndrome Due to Prostate Cancer: A Case Series

Background: The introduction of chemotherapy and androgen receptor signaling inhibitors to patients with newly diagnosed metastatic or castration resistant prostate cancer has resulted in longevity and improved quality of life. However, as the disease transitions to a more resistant clinical state despite multiple agents, there has been, in some patients, the emergence of a more aggressive form of the disease with adrenocorticotropic hormone (ACTH) production due to either small cell or neuroendocrine features. These subtypes of prostate cancer are behaviorally unique and can manifest with clinical symptoms and laboratory abnormalities due to severe hypercortisolemia that portend rapid clinical decline if not death. In order to facilitate early recognition and treatment of this rare clinical syndrome, we describe several cases of ectopic ACTH-dependent Cushing’s syndrome that were associated with this histologic entity and were not easily identified despite refractory hypokalemia and hypertension. Methods: Through a dataline search we identified 10 cases of prostate cancer with ectopic ACTH-dependent Cushing’s syndrome treated at MSKCC over the past 20 years. Data were abstracted from patients' medical records, including clinical course, histopathology and response to therapy. Results: Mean age at presentation was 66 years (range 58 to 80). 9 of 10 patients reported prior tobacco use. 7 of 10 patients had prostate adenocarcinoma prior to diagnosis of ectopic Cushing’s, and 9 of 10 patients had a Gleason score >7. When available, tumor pathology showed small cell or high grade neuroendocrine carcinoma, but despite elevated plasma ACTH levels, not all tumors had immunohistochemistry that was positive for ACTH. Spontaneous hypokalemia was present in all 10 patients, and presenting signs of Cushing’s syndrome were most commonly hypokalemia or resistant hypertension. One patient had hypertensive urgency and two developed psychosis. Median survival was ~2.5 months after the development of Cushing’s syndrome. Four patients died of complications from progressive tumor growth, and three died of complications due to infections, including PCP, aspergillus lung infection, mold lung infection, cellulitis/fasciitis, and mastoiditis. Three died of unclear causes. Conclusions: Prostate cancer that evolves into an ACTH-secreting neuroendocrine phenotype is a rare entity that is associated with high risk for infections, refractory hypokalemia, and poor survival. Further clinical and pathological characterization is needed to ensure early recognition and appropriate treatment interventions for these patients.

Pituicytoma Associated with Serum Adrenocorticotropic Hormone Elevation

Background: Pituicytoma is a rare benign tumor of the neurohypophysis or hypophyseal stalk. Endocrinological abnormalities derived from this tumor are even rarer. Although three cases of pituicytoma with elevated plasma adrenocorticotropic hormone (ACTH) have been reported previously, the etiological mechanisms remain unknown. Case Description: We present a 47-year-old woman who was referred to a hospital complaining of headache. On investigation using magnetic resonance imaging (MRI), a tumor was detected in the sellar region. Elevation of basal ACTH and serum cortisol was identified, suggesting an ACTH-producing pituitary adenoma. However, physical findings and results of other hormonal examination showed no evidence of Cushing disease. The tumor had been detected incidentally eight years earlier when MRI was performed, and showed considerable enlargement on this consultation. Endoscopic endonasal transsphenoidal surgery was performed in order to remove the tumor completely. The histopathological diagnosis was pituicytoma. The patient’s postoperative clinical course was excellent, and both ACTH and cortisol levels returned to normal following surgery. Conclusions: It appears that ACTH was being secreted from the tumor cells. We discuss the possible mechanism of ACTH elevation in cases of pituicytoma.

Bilateral inferior petrosal sinus sampling using vasopressin

Context:Anatomical localization of pituitary adenoma can be challenging in adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, and bilateral inferior petrosal sinus sampling (BIPSS) is considered gold standard in this regard. Stimulation using corticotrophin-releasing hormone (CRH) improves the sensitivity of BIPSS, however, same is not easily available in India. Therefore, we undertook this study of BIPPS using vasopressin as agent for stimulation owing to its ability to stimulate V3 receptors present on corticotrophs.Aims:To study the tumor localization and lateralization in difficult to localize cases of ACTH-dependent Cushing's syndrome by bilateral inferior petrosal sinus sampling using vasopressin for corticotroph stimulation.Settings and Design:Prospective observational study.Subjects and Methods:Six patients (5 females) meeting inclusion criteria underwent BIPSS using vasopressin for stimulation.Results:All six patients had nonsuppressible overnight and low dose dexamethasone suppression test with elevated plasma ACTH levels suggestive of ACTH-dependent Cushing's syndrome. High dose dexamethasone suppression test showed suppressible cortisol in two cases, and microadenoma was seen in two patients on magnetic resonance imaging pituitary. Contrast enhanced computed tomography of the abdomen showed left adrenal hyperplasia in one case and anterior mediastinal mass with bilateral adrenal hyperplasia another. Using BIPSS four patients were classified as having Cushing's disease that was confirmed histopathologically following surgery. Of the remaining two, one had primary pigmented nodular adrenocortical disease, and another had thymic carcinoid with ectopic ACTH production as the cause of Cushing's syndrome. No serious adverse events were noted.Conclusions:Vasopressin may be used instead of CRH and desmopressin for stimulation in BIPSS.

Three Cases of ACTH-Producing Pheochromocytoma – Full Hormonal Workup in Patients With an Adrenal Mass May Be Crucial For Correct Management

ABSTRACT Objective: In rare cases, adrenal medullary tumors secrete adrenocorticotropic hormone (ACTH) in addition to catecholamines. Methods: We present 3 cases of ACTH-producing pheochromocytomas, highlighting the diagnostic challenges, clinical severity, and phenotypic diversity of this rare phenomenon. Results: Two of the patients (females aged 75 and 60 years) presented with typical Cushingoid phenotypes. Their biochemical profiles were consistent with ectopic ACTH-dependent Cushing syndrome with grossly elevated plasma ACTH and urinary free cortisol. One of the patients had vague symptoms of adrenergic hyperactivity and highly elevated levels of plasma metanephrines, whereas the other had no symptoms of pheochromocytoma. The third patient (male aged 64 years) presented with tachycardia, labile blood pressure, and sweating consistent with pheochromocytoma. He had no signs of Cushing syndrome. Plasma and urine samples showed highly elevated concentrations of catecholamines, ACTH, and cortisol. After admission to hospital, all patients deteriorated within a few weeks with multiorgan involvement. All 3 had unilateral adrenal masses, and acute rescue adrenalectomy was performed. Histopathologic examination showed pheochromocytomas with positive ACTH immunostaining. The patients recovered quickly after surgery with restoration of organ functions. Conclusion: Extensive hormone profile evaluations should be carried out in all adult patients presenting with an adrenal mass independent of the clinical presentation. ACTH-producing pheochromocytoma should be considered in patients presenting with the confusing picture of ACTH-dependent Cushing syndrome and a unilateral adrenal mass. Abbreviations: ACTH adrenocorticotropic hormone CT computed tomography MRI magnetic resonance imaging P plasma T2DM type 2 diabetes mellitus

Periodic hypokalemia associated with cyclic Cushing's syndrome.

A 69-year-old woman presented with periodic hypertension, edema, and hypokalemia that occurred within an interval of a few weeks. Her laboratory test values showed autonomously elevated plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. The patient's Cushingoid features were not evident on first admission. Several weeks later, in spite of constant oral potassium supplementation, severe hypokalemia recurred with Cushingoid features and worsening symptoms of leg edema and pigmentation, which spontaneously disappeared within a few days. Her periodic symptoms occurred in parallel with fluctuations of plasma ACTH and cortisol concentrations. A series of endocrinological and pituitary imaging findings led to a tentative diagnosis of cyclic Cushing's syndrome caused by ectopic ACTH secretion. However, chest and abdominal computed tomography did not reveal any candidate lesion. The patient's periodic hypercortisolemia and symptoms were well controlled after treatment with metyrapone plus dexamethasone. This is a very rare case of periodic hypokalemia and hypertension caused by cyclic Cushing's syndrome.

Antidiuretic response of a horse affected with pituitarypars intermediadysfunction to desmopressin acetate

Summary Central diabetes insipidus (DI) was diagnosed in a 20-year-old American Quarter Horse gelding that was concomitantly affected with pituitary pars intermedia dysfunction (PPID). The diagnosis of DI was supported by a positive response to administered desmopressin acetate. Diagnosis of PPID was supported by physical appearance and elevated plasma adrenocorticotropic hormone concentration following domperidone administration. The horse's physical condition improved following treatment with pergolide but long-term treatment with desmopressin was not undertaken and severe polyuria and polydipsia persisted. Desmopressin acetate appears to be useful for the diagnosis of DI in mature horses concomitantly affected with PPID.

The impact of maternal overnutrition and obesity on hypothalamic-pituitary-adrenal axis response of offspring to stress

We evaluated the effect of maternal obesity before and throughout gestation on offspring hypothalamic-pituitary-adrenal axis function. Multiparous Rambouillet by Columbia crossbred ewes were fed either 100% of National Research Council (NRC) recommendations (control, C) or 150% of NRC recommendations (obese, OB) from 60 d before mating until lambing. Ten lambs born to OB ewes (five males and five females), and eight lambs born to C ewes (three male and five female) were studied. From delivery to weaning lambs were maintained with their mothers, who were all fed 100% NRC recommendations. After weaning, all lambs were group housed and fed the same diet to meet NRC requirements. At 19 mo of age lambs were placed in individual pens and fed a pelletized diet to meet maintenance requirements. Jugular vein catheters were placed and 2 d later lambs received an intravenous (i.v.) adrenocorticotropic hormone (ACTH) challenge followed by an i.v. corticotropin-releasing hormone (CRH)/arginine vasopressin (AVP) challenge 1 d later. Thirty d later offspring were again catheterized and placed into metabolism crates for 2 d before receiving an isolation stress test. ACTH and cortisol responses to the isolation stress test and CRH/AVP challenge and cortisol responses to ACTH challenge were determined. Cortisol was quantified via radioimmunoassay and ACTH was quantified using an Immulite 1000; both were analyzed using repeated measures using the MIXED procedure of SAS. Offspring from OB ewes had elevated basal plasma ACTH and cortisol compared with C offspring before all three challenges (P < 0.05). Offspring from OB mothers tended (P = 0.06) to have a greater ACTH response after an i.v. CRH/AVP injection than offspring from C mothers (12,340 ± 1,430 vs 8,170 ± 1,570 area under the curve, respectively). Cortisol response to the CRH/AVP and ACTH challenges was not influenced by maternal nutrition (P = 0.46) and averaged 4.77 ± 0.2 μg/dL and 1.94 ± 0.01 μg/dL, respectively. The ACTH response following the isolation stress test was also similar (P = 0.82) for OB and C offspring (147 ± 20 pg/mL), and cortisol response during the isolation stress test was similar between C and OB offspring (P = 0.64, 5.25 ± 0.3 μg/dL). These findings suggest that maternal obesity before and during gestation does not affect stress responses by the offspring, but has an impact on hypothalamic-pituitary-adrenal sensitivity. The lack of differences in cortisol release under the influence of difference concentrations of ACTH during the CRH/AVP challenge could indicate adrenal dysfunction in OB offspring.

Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in adolescence. Report of three siblings

Background:Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by glucocorticoid deficiency, high ACTH levels and normal mineralocorticoid levels. FGD is caused due to defects in adrenocorticotropic hormone (ACTH) signaling. The defect can be caused by mutations in genes encoding the ACTH receptor (melanocortin 2 receptor) or its accessory protein.Patients:Here we report three siblings with FGD. The second in order of siblings presented at an age of 15 years with history of diffuse hyperpigmentation since childhood. Their parents were non consanguineous. The patients were hyperpigmented and taller compared with their parents. None of the siblings had ambiguous genitalia or neurological abnormalities. There was no history of tuberculosis in the family. Biochemical investigations revealed low serum cortisol (<1 μg/dl) and elevated plasma ACTH (>1250 pg/ml). Serum electrolytes, aldosterone, and plasma renin activity was normal. Based on the above mentioned data, a provisional diagnosis of FGD was made after ruling out the common causes of glucocorticoid deficiency.Conclusion:FGD is a rare autosomal recessive disorder which causes isolated glucocorticoid deficiency. Unawareness about the condition may lead to delayed diagnosis and treatment, which are associated with high rates of morbidity and mortality. Once a diagnosis is made it is easily treatable.

Clinical Characteristics of Taiwanese Children With Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency in the Pre-screening Era

Data about the clinical manifestations of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21-OHD) are lacking in Taiwan. Therefore, this study analyzed the clinical features of 21-OHD in Taiwanese children to improve the diagnosis of this disorder, and to provide background information regarding the ongoing neonatal screening program for 21-OHD in Taiwan. Eighty children with 21-OHD, 39 with the salt-wasting (SW) type and 41 with the simple-virilizing (SV) type, were evaluated by a review of their medical records. Their clinical symptoms and signs, laboratory findings, and genetic mutations were analyzed. The most frequent features in 21-OHD patients were hyperpigmentation and signs of androgen excess. Clinical manifestations related to hyponatremia such as poor feeding, poor weight gain, and dehydration were noted most frequently in patients with SW-type 21-OHD. Five patients had low serum cortisol with elevated plasma adrenocorticotropic hormone levels, and 22 patients had elevated dehydroepiandrosterone sulfate levels. All had elevated blood levels of 17-hydroxyprogesterone, androstenedione and testosterone. Hyponatremia and hyperkalemia were detected in 29 patients with SW-type 21-OHD. In terms of molecular diagnosis, mutations at IVS2-12A/C --> G and gene deletion were the most frequent mutations detected in SW-type 21-OHD, while I172N and mutation at IVS2-12A/C --> G were most frequent in SV type. Taiwanese children with 21-OHD have characteristic clinical findings such as hyperpigmentation, androgen excess, and failure to thrive. There is a good correlation between genotype and pheno-type. Laboratory tests, including serum 17-hydroxyprogesterone, androstenedione, and testosterone levels are more sensitive than serum cortisol or dehydroepiandrosterone sulfate levels for diagnosing 21-OHD in prepubertal children.

A Case of Ectopic Adrenocorticotropic Hormone-producing Pancreatic Neuroendocrine Tumor with Multiple Liver Metastases

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.